It is estimated that 10 percent of the population is affected by sensorineural or "nerve" deafness that usually arises from sensory hair-cell loss or damage. Sensory deficits resulting from hair-cell loss have been considered irreversible because the production of human hair cells ceases before birth. In contrast, hair cells are produced postembryonically in the ears of cold-blooded and some warm-blooded vertebrates (birds); in some, thousands of new hair cells can be replaced through trauma-evoked regenerative proliferation. Recent evidence has shown that supporting cells proliferate and that new hair bundles can appear in vivo in the balance organs of mammals after antibiotic poisoning of hair cells. Also, supporting cells proliferate after the death of hair cells in organ cultures taken from the adult human ear. These findings suggest that hair-cell regeneration may be induced in the ears of humans. In order to develop clinical therapies that will bring about hair-cell regeneration in the human ear, we must identify the cellular and molecular signals responsible for triggering the regenerative proliferation of inner-ear supporting cells after hair-cell death, and determine how these cells go on to form hair cells. The goal of the proposed research is to identify factors that trigger regenerative replacement of hair cells in the ears of warm-blooded vertebrates during postembryonic life. This application proposes to investigate two hypotheses: (1) that growth factors are important in initiating and regulating the hair-cell regeneration response; and (2) that leukocytes are important in initiating hair-cell regeneration, perhaps through their release of growth factors. These hypotheses will be tested using a combination of techniques, including cell culture, immunocytochemistry, scanning and transmission electron microscopy, transfection, in situ hybridization, and the use of transgenic mice.